BIOMATERIALS
·
2022
·
IF 15.304
Yan Gao,Zilin Song,Li Jia,Yi Tang,Chengcheng Wang,Xiuli Zhao,Haiyang Hu,Dawei Chen,Mingxi Qiao
Despite the important role of reactive oxygen species (ROS) in battling cancer, ROS production with current approaches has been severely limited by the deficiency of oxy-substrates in tumor microenvironment . Herein, an atorvastatin (Ato)-catalytic self-amplified approach was utilized for sustainable ROS production and enhancing anti-tumor efficacy of PD-L1 silencing. A C 18 -pArg 8 -ss-pHis 10 lipopeptide based self-assembled nanoplexes was developed to co-encapsulate AMP-activated protein kinase (AMPK) activator of Ato and PD-L1 siRNA. Efficient delivery of payloads was achieved because of the acidic pH triggered the protonation of pHis 10 , disulfide-bond exposure for cleavage and subsequent cytosolic translocation. Ato was found to activate AMPK, boosting the highly restrained mitochondrial fatty acid oxidation (FAO) in cancer cells for ROS production. The ROS derived from FAO further activated AMPK, creating a positive-feedback mechanism of sustainable ROS production. The self-amplified ROS production from cellular mitochondrial FAO was maintained by the sufficient intracellular fatty acid substrates arising from the dysregulated lipid metabolism and Ato inhibited triglyceride synthesis in cancer cells. The excessive ROS level was found to successfully induce immunogenic cell death effect, boosting the anti-tumor efficacy of PD-L1 silencing. Overall, the Ato catalyzed self-amplified ROS production has been demonstrated as a promising alternative for cancer therapy.
研究领域:
癌症治疗
·
药学
·
免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioanalysis
·
2023
·
IF 1.8
Yuhuan Ji,Zhaoxu Guo,Min Yan,Limin Chu,Min Meng,Yantao Chu,Hong Yu,Laixin Wang
Aim: RBD1016 is an N-acetylgalactosamine-conjugated siRNA drug currently in a phase II trial for treatment of chronic hepatitis B virus. To evaluate its absorption, distribution, metabolism and excretion (ADME) and pharmacokinetic/pharmacodynamic (PK/PD) properties, two LC-based bioanalytical methods, LC–high-resolution/accuracy MS and LC–fluorescence detection, were developed and qualified. Materials & methods: The LC–high-resolution/accuracy MS method was used for metabolite identification and simultaneous quantitation of the antisense and sense strands as well as their respective metabolites. The LC–fluorescence detection assay was primarily used for analyzing the antisense strand and its metabolites in low-concentration plasma samples. The two methods were successfully bridged by analyzing the same sets of study samples. Results & conclusion: Both methods were found to have excellent accuracy/precision, specificity and reproducibility to support ADME and PK/PD studies of RBD1016 siRNA.
研究领域:
药学
·
分析化学
·
药理学
·
病毒学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2018
·
IF 7.877
Huipeng Li,Xue Yang,Fang Gao,Chenggen Qian,Chenzi Li,David Oupicky,Minjie Sun
In present study, gene concentrated as well as bioreduction-ruptured nanogel with local enrichment positive charge while low cytotoxicity was developed for Bcl2 siRNA delivery featured in intracellular switch on/off controlled release. Dynamic covalent bond crosslinked nanogel was formed by thiolated PEI of 1.8 kDa(PEI-1.8 kDa)and biodegradable dextrin . Once nanogel was uptake by tumor cells, high concentration of glutathione (GSH) in cytosol could bioreducible -degrade and rupture the crosslink of this dextrin nanogel (DSP) into hypotoxic PEI-1.8 kDa and dextrin, following by burst release of packed siRNA and minimizing the restriction of polymer material for siRNA transcription. This switch on/off siRNA release strategy for gene therapy exhibited equal level of the deregulation of Bcl2 protein expression determined by western blot analysis compared with cationic PEI with 25 kDa molecular weight (PEI-25 kDa) in vitro . Moreover, the gene concentrated DSP based on hypotoxic PEI-1.8 kDa and biodegradable dextrin could be administrated intravenously for systematic therapy on safely. Tumor suppression study of DSP also exhibited a superior antitumor activity in 4T1-luc tumor cell bearing BALB/C mice. Furthermore, it exhibited lower cytotoxicity, almost none hemotoxicity , moreover avoiding recognition and clearance by RES system in healthy mice. Overall, these findings suggest that this reduction-sensitive while bioreduction-ruptured polymer nanogel is an innovative strategy and holds great promise for gene and drug delivery.
研究领域:
癌症治疗
·
基因递送
·
纳米技术
·
药学科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2014
·
IF 5.9
Haiyan Zhu,Chunyan Dong,Haiqing Dong,Tianbin Ren,Xuejun Wen,Jiansheng Su,Yongyong Li
Polylysine with cleavable PEGylation and hydrophobic histidylation (mPEG-SS-Lysn-r-Hism) was designed and developed for efficient siRNA delivery and tumor therapy. mPEG-SS-Lysn-r-Hism was used to carry and deliver small interfering RNA (siRNA) for silencing endogenous vascular endothelial growth factor (VEGF) expression and inhibiting tumor growth in HepG2 tumor-bearing mice. In this gene vector, histidine(Bzl) was selected for hydrophobic histidylation for the proton sponge ability of the imidazole ring and hydrophobic benzyl group. Cleavable PEGylation was introduced for in vivo circulation as well as selective PEG detachment in response to intracellular reduction condition in order to release the genetic payload. PEG detachment induced gene release was supported by agarose gel electrophoresis retardation assay, undertaken in the intracellular relevant reduction condition. In vitro transfection evaluation of histidylated copolymers, using pEGFP as genetic model, indicated significantly higher GFP expression than unmodified counterparts, comparable to the gold standard PEI. The efficacy of hydrophobic histidylation was found to be pronounced in mesenchymal stem cells (MSCs). In vivo application of the VEGF-siRNA package by tailored mPEG-SS-Lysn-r-Hism showed distinct tumor suppression in terms of macroscopic tumor volume and molecular analysis.
研究领域:
药学
·
分子生物学
·
基因治疗
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2017
·
IF 6.319
Jing Wang,Lifei Xie,Tao Wang,Fengxin Wu,Jie Meng,Jian Liu,Haiyan Xu
Cationic macromolecules are attractive for use as small interfering RNA (siRNA) carriers due to their performance in non-immunological reactions, customization during synthesis, and low costs compared to viral carriers. However, their low transfection efficiency substantially hinders their application in both clinical practices and academic research, which is mostly attributable to the low capacity of siRNA/cationic macromolecule complexes to escape lysosomes . To address this challenge, we designed an amphiphilic fullerene derivative (C 60 -Dex-NH 2 ) for efficient and controllable siRNA delivery. To synthesize C 60 -Dex-NH 2 , terminally aminated dextran was conjugated to C 60 . The conjugate was further cationized by covalently introducing ethylenediamine to the dextran. The physicochemical characteristics of C 60 -Dex-NH 2 was examined with elemental analyses, gel permeation chromatography , solid-state nuclear magnetic resonance ( 13 C, HPDEC), agarose gel electrophoresis , and dynamic light scattering . The cytotoxicity, cellular uptake, intracellular distribution , and in vitro RNA interference (RNAi) of siRNA/C 60 -Dex-NH 2 complex was evaluated in the human breast cancer cell line MDA-MB-231. The RNAi efficiencies mediated by C 60 -Dex-NH 2 in vivo was evaluated in subcutaneous tumor-bearing mice. The results showed that C 60 -Dex-NH 2 has a specific amphiphilic skeleton and could form micelle-like aggregate structures in water, which could prevent siRNA from destroying by reactive oxygen species (ROS). When exposed to visible light, C 60 -Dex-NH 2 could trigger controllable ROS generation which could destroy the lysosome membrane, promote the lysosomal escape, and enhance the gene silencing efficiency of siRNA in vitro and in vivo . The gene silencing efficiency could reach a maximum of 53% in the MDA-MB-231-EGFP cells and 69% in the 4T1-GFP-Luc2 tumor-bearing mice. Statement of Significance We designed a novel photosensitive amphiphilic carrier (C 60 -Dex-NH 2 ) for efficient and controllable siRNA delivery, which can be used in gene therapy. We showed that C 60 -Dex-NH 2 could destroy lysosome membrane via controllable generation of ROS when exposed to light, which can help siRNA to escape from lysosome before degradation. This can enhance the gene silencing efficiency significantly and provides a useful way to regulate RNAi efficiency by light. One advantage for C 60 -Dex-NH 2 system is C 60 has broad absorbance spectrum and can be activated by weak visible light; Furthermore, C 60 -Dex-NH 2 has a specific amphiphilic structure, which may prevent siRNA from degrading and allows C 60 -Dex-NH 2 to embed into the lipid membrane of lysosome to improve the ROS induced lysosomal disturbance after internalization .
研究领域:
药学
·
纳米技术
·
分子生物学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2019
·
IF 6.638
Na Li,Liqun Yang,Chenglin Pan,Phei Er Saw,Meng Ren,Biyun Lan,Junfeng Wu,Xiaoyi Wang,Tingting Zeng,Liyan Zhou,Li-Ming Zhang,Chuan Yang,Li Yan
s The anomalous high expression of matrix metalloproteinase 9 (MMP-9) is one important factor that impedes diabetic wound healing. Therefore, inhibition of MMP-9 expression in a diabetic wound could be a feasible method to promote wound healing. In this study, we studied the possibility of self-therapy using wound dressings that contain bacterial cellulose-hyperbranched cationic polysaccharide (BC-HCP) derivatives that encapsulate siRNA (BC-HCP/siMMP-9) and have controlled release properties. Herein, we used four HCPs (Gly-DMAPA, Gly-D4, Amyp-DMAPA, Amyp-D4) as gene carriers. Our results showed that all HCP derivatives were minimally toxic to cells in vitro , while the cationic properties of HCP could be used as a complexation agent for MMP-9 siRNA (siMMP-9). Upon exposure to bacterial cellulose (BC), the BC slowly released HCP/siMMP-9. The released siMMP-9 effectively reduced the gene expression and protein levels of MMP-9 in a human immortalized epithelial cell line (HaCAT) and in diabetic rat wounds. Inhibition of MMP-9 in the wounds of diabetic rats resulted in a significant enhancement of wound healing, suggesting that the BC-HCP/siMMP-9 composite dressing could be used as a safe and effective dressing to promote wound healing in diabetic rats. Statement of significance In this work, we evaluated the possibility of using bacterial cellulose-hyperbranched cationic polysaccharide derivatives (BC-HCP) as a self-therapeutic wound dressing with siRNA encapsulated and controlled release properties. Our results showed that the BC-HCP/siMMP-9 composite dressing slowly released HCP/siMMP-9. The released siMMP-9 effectively reduced the gene expression and protein level of MMP-9 in human immortalized epithelial cell line and in the wound of diabetic rats. The BC-HCP/siMMP-9 composite dressing promoted diabetic wound healing by the unique nanostructure of BC and by releasing siMMP-9 for specific MMP-9 inhibition. Therefore, it could be used as a safe and effective dressing to promote wound healing in diabetic rats. This is the first evidence on the study of using BC as a dressing composite by encapsulating HCP/siRNA complexes for efficient RNAi gene silencing for better wound healing in diabetic rats.
研究领域:
生物医学工程
·
药剂学
·
伤口愈合
·
糖尿病
·
基因治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2020
·Vol. 8
·期 7
·1507-1515
·
IF 5.344
Kai Xu,Zhenghuan Zhao,Junfeng Zhang,Wei Xue,Haipeng Tong,Heng Liu,Weiguo Zhang
Mn(IV)-Based nanoparticles (NPs) are effective in improving tumor oxygenation (hypoxia) and reducing endogenous hydrogen peroxide and acidity in the tumor region. However, the optimized reduction conditions of conventional Mn(IV)-based NPs are generally reported at pH ≤ 6.5, while the usual pH range of the tumor microenvironment (TME) is 6.5–7.0. The dissatisfactory imaging performance in the weakly acidic environment may limit their further application in tumor diagnosis. In this study, Mn(III) was introduced in a nanoplatform, because it is reduced into Mn(II) in weakly acidic environments. Arg-Gly-Asp (RGD) peptide-decorated bovine serum albumin (BSA) was employed as the stabilizer and scaffold to fabricate Mn(III)- and Mn(IV)-integrated nanocomposites (RGD-BMnNPs) with suitable size, good stability, and excellent biocompatibility. The as-prepared NPs showed clear contrast enhancement at pH 6.5–6.9 in vitro as well as sensitive and rapid T1-weighted imaging performance within the tumor region in a glioblastoma (U87MG) orthotopic model, owing to the intrinsic disproportionation reaction of Mn(III) in the weakly acidic environment. In addition, these NPs could be used for efficient siRNA delivery. They showed superior advantages in this process, including increased tumour uptake, improved tumor accumulation and enhanced therapeutic effects with the modulation of the TME. These novel albumin-stabilized manganese-based NPs combined with efficient drug delivery capacity hold great potential to serve as intelligent theranostic agents for further clinical translation.
研究领域:
生物医学工程
·
纳米技术
·
癌症研究
·
神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-21
·
IF 10.6
Wu Zhen,Zhang Peng,Yue Jie,Wang Qingshan,Zhuang Peipei,Jehan Shah,Fan Liyuan,Xue Jiarun,Zhou Wenhu,Wang Haiyang
Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease, while there is a lack of pharmaceutical interventions to halt AAA progression presently. To address the multifaceted pathology of AAA, this work develops a novel multifunctional gene delivery system to simultaneously deliver two siRNAs targeting MMP-2 and MMP-9. The system (TPNs-siRNA), formed through the oxidative polymerization and self-assembly of epigallocatechin gallate (EGCG), efficiently encapsulates siRNAs during self-assembly. TPNs-siRNA safeguards siRNAs from biological degradation, facilitates intracellular siRNA transfection, promotes lysosomal escape, and releases siRNAs to silence MMP-2 and MMP-9. Additionally, TPNs, serving as a multi-bioactive material, mitigates oxidative stress and inflammation, fosters M1-to-M2 repolarization of macrophages, and inhibits cell calcification and apoptosis. In experiments with AAA mice, TPNs-siRNA accumulated and persisted in aneurysmal tissue after intravenous delivery, demonstrating that TPNs-siRNA can be significantly distributed in macrophages and VSMCs relevant to AAA pathogenesis. Leveraging the carrier’s intrinsic multi-bioactive properties, the targeted siRNA delivery by TPNs exhibits a synergistic effect for enhanced AAA therapy. Furthermore, TPNs-siRNA is gradually metabolized and excreted from the body, resulting in excellent biocompatibility. Consequently, TPNs emerges as a promising multi-bioactive nanotherapy and a targeted delivery nanocarrier for effective AAA therapy.Graphical Abstract
研究领域:
纳米技术
·
基因治疗
·
血管生物学
·
药学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2019
·Vol. 7
·期 8
·3307-3319
·
IF 5.251
Bin Gao,Qiaoping Zhang,Xiaoyu Wang,Meiyu Wang,Xiang-kui Ren,Jintang Guo,Shihai Xia,Wencheng Zhang,Yakai Feng
Small interfering RNA (siRNA)-based therapy is an emerging treatment to address serious cardiovascular disease. It is essential to construct highly efficient vehicles for therapeutic siRNA intracellular delivery. Extracellular signal-regulated kinase-2 (ERK2) siRNA (abbreviated as ERK2-siRNA) is known as a type of siRNA to selectively silence the expression of ERK2. Herein, a type of ternary delivery system characterized by an endosome-selective-self-accelerating-escape ability was designed and prepared for the purpose of inhibiting the migration of vascular smooth muscle cells (VSMCs) in vitro. This system was called ternary ERK2-siRNA complexes (abbreviated as TRCs-Aco), which were fabricated via sequential electrostatic self-assembly of a star-shaped cell-penetrating peptide based on polyhedral oligomeric silsesquioxane (POSS-(C-G-R8-G-W)16), ERK2-siRNA and a pH-sensitive anionic polymer of cis-aconitic anhydride grafted ε-poly(L-lysine). Importantly, TRCs-Aco could break down the obstacle of biocompatibility-silencing efficiency. In comparison with the parent binary siRNA complexes (abbreviated as BRCs), which are composed of POSS-(C-G-R8-G-W)16 and ERK2-siRNA, our designed TRCs-Aco revealed more excellent biocompatibility including hemocompatibility and cytocompatibility. Unexpectedly, TRCs-Aco exhibited stronger ERK2 silencing efficiency at the level of mRNA and protein, which was mainly due to its remarkable self-accelerating endosomal escape. Definitive evidence demonstrated that this ternary ERK2-siRNA delivery system significantly prevented the migration of VSMCs and decreased the dermal thickness in bleomycin-treated mice. In brief, this unique structured system could provide a valuable nanoplatform for highly efficient siRNA delivery in VSMCs, and it might hold great potential in guiding ERK2-siRNA-based proliferative disease therapy.
研究领域:
纳米技术
·
药学
·
心血管疾病
·
分子生物学
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOMATERIALS APPLICATIONS
·
2024
·
IF 2.3
Guojie Lu,Huiling Zhong,Jianwei Gao,Yaosen Zhang
The long non-coding RNA HOTAIR and the Hedgehog-Gli1 signaling pathway are closely associated with tumor occurrence and drug resistance in various cancers. However, their specific roles in the development of EGFR-TKIs resistance in non-small cell carcinoma remain unclear. To address the issue of EGFR-TKIs resistance, this study utilized the electrospray method to prepare sodium alginate microspheres encapsulating HOTAIR siRNA (SA/HOTAIR siRNA) and investigated its effects on RNA interference (RNAi) in the gefitinib-resistant cell line PC9/GR. Furthermore, the study explored whether HOTAIR could modulate EGFR-TKIs resistance through the Hedgehog-GLi1 signaling pathway. The experimental results showed that sodium alginate (SA) microspheres demonstrated excellent biocompatibility with high encapsulation efficiency and drug-loading capacity, effectively enhancing the silencing efficiency of siRNA. HOTAIR siRNA significantly inhibited the proliferation, migration, and invasion abilities of PC9/GR cells while promoting apoptosis. Additionally, HOTAIR siRNA effectively suppressed tumor growth and downregulated the Hedgehog-GLi1 pathway and anti-apoptotic proteins, which were confirmed in animal experiments. Moreover, SA/HOTAIR siRNA exhibited superior inhibition of cellular and tumor functions compared to using HOTAIR siRNA alone. Clinical research findings indicated that monitoring the expression level of HOTAIR in the serum and urine samples of NSCLC patients before and after receiving EGFR-TKIs treatment can predict the efficacy of EGFR-TKIs to a certain extent. This study provided evidence that HOTAIR siRNA effectively mitigated the development of acquired resistance to EGFR-TKIs by inhibiting the Hedgehog-GLi1 pathway. Furthermore, it introduced a reliable and long-lasting drug delivery system for combating acquired resistance to EGFR-TKIs.
研究领域:
肿瘤学
·
分子生物学
·
药学
·
癌症治疗
✓ 已验证
DOI
PubMed
高影响因子
Matter
·
2022
·
IF 19.967
Yunfei Yi,Mian Yu,Chan Feng,Huisong Hao,Weiwei Zeng,Chuchu Lin,Hongzhong Chen,Feng Lv,Dunwan Zhu,Xiaoyuan Ji,Lin Mei,Meiying Wu,Wei Tao
Summary It is highly desirable to turn “cold” tumors into “hot” ones to improve the efficacy of antitumor immunotherapy. Herein, we develop the peptide-based small interfering RNA (siRNA) micelleplexes (P A7R @siPD-L1) for normalizing vascular-immune crosstalk to establish a positive feedback loop in potentiating antitumor immunotherapy. These micelleplexes are equipped with tumor-microenvironment-responsive property for precise drug delivery and release. The prepared P A7R @siPD-L1-mediated photodynamic therapy could eliminate solid tumors and trigger immunogenic cell death to generate systematic immune responses. Meanwhile, the antiangiogenic peptide A7R normalizes the tumor vasculature by converting chaotic vascular systems into matured and organized ones, thus alleviating tumor hypoxia and promoting intratumoral infiltration by immune cells. Antitumor immunogenicity would be further strengthened with the aid of siPD-L1 by muting the resistance of tumor cells against immune effector cells. This study provides a unique therapeutic strategy in turning “cold” tumors into “hot” tumors enabled by siRNA nanomaterial .
研究领域:
肿瘤学
·
免疫疗法
·
纳米医学
·
癌症生物学
✓ 已验证
DOI
高影响因子
Nanoscale
·
2013
·Vol. 5
·期 10
·4291-4301
·
IF 6.233
Daoshu Lin,Qiang Cheng,Qian Jiang,Yuanyu Huang,Zheng Yang,Shangcong Han,Yuning Zhao,Shutao Guo,Zicai Liang,Anjie Dong
A low cytotoxicity and high efficiency delivery system with the advantages of low cost and facile fabrication is needed for the application of small interfering RNA (siRNA) delivery both in vitro and in vivo. For these prerequisites, cationic polymer–mesoporous silica nanoparticles (ssCP-MSNs) were prepared by surface functionalized mesoporous silica nanoparticles with disulfide bond cross-linked poly(2-dimethylaminoethyl methacrylate) (PDMAEMA). In vitro and in vivo evaluations were performed. The synthesized ssCP-MSNs are 100–150 nm in diameter with a pore size of 10 nm and a positively charged surface with a high zeta potential of 27 mV. Consequently, the ssCP-MSNs showed an excellent binding capacity for siRNA, and an enhancement in the cell uptake and cytosolic availability of siRNA. Furthermore, the intracellular reducing cleavage of the disulfide bonds cross-linking the PDMAEMA segments led to intracellular cleavage of PDMAEMA from ssCP-MSNs, which facilitated the intracellular triggered release of siRNA. Therefore, promoted RNA interference was observed in HeLa-Luc cells, which was equal to that of Lipofectamine 2000. Significantly, compared to Lipofectamine 2000, the ssCP-MSNs were more biocompatible, with low cytotoxicity (even non-cytotoxicity) and promotion of cell proliferation to HeLa-Luc cells. The in vivo systemic distribution studies certified that ssCP-MSNs/siRNA could prolong the duration of siRNA in vivo, and that they accumulated in the adrenal gland, liver, lung, spleen, kidney, heart and thymus after intravenous injection. Encouragingly, with the ability to deliver siRNA to a tumor, ssCP-MSNs/siRNA showed a tumor suppression effect in the HeLa-Luc xenograft murine model after intravenous injection. Therefore, the ssCP-MSNs cationic polymer–mesoporous silica nanoparticles with low cytotoxicity are promising for siRNA delivery.
研究领域:
纳米技术
·
药学
·
分子生物学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）